US11497734B2ActiveUtilityA1
Dual inhibitors of TIM-3 and PD-1 pathways
Est. expiryNov 3, 2037(~11.3 yrs left)· nominal 20-yr term from priority
Inventors:Pottayil Govindan Nair SasikumarMuralidhara RamachandraSeetharamaiah Setty Sudarshan NaremaddepalliNagaraj Gowda
A61P 31/00C07D 271/06A61P 35/00Y02A50/30A61K 31/4245A61K 45/06A61K 31/5377A61K 31/454
91
PatentIndex Score
11
Cited by
152
References
29
Claims
Abstract
The present disclosure relates to 3-substituted 1,2,4-oxadiazole compounds and their derivatives, which are useful as T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) inhibitors or as dual inhibitors of TIM-3 and the programmed cell death 1 (PD-1) signaling pathway. The disclosure also relates to treatment of disorders by inhibiting an immunosuppressive signal induced by TIM-3, PD-1, PD-L1, and/or PD-L2.
Claims
exact text as granted — not AI-modifiedWe claim:
1. A method of modulating an immune response mediated by T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) activity in a subject, comprising administering to the subject compound of Formula (I), or a pharmaceutically acceptable salt thereof:
wherein:
Z represents —OH or —NH-G;
G represents hydrogen or (C 1 -C 6 )alkyl;
Y represents hydrogen or a group represented by the following structural formula
R a represents (C 1 -C 6 )alkyl substituted with —OH, —NR x R y , —SR x , carboxylic acid, guanidino, or aryl, wherein the aryl group is optionally further substituted with hydroxyl; or R a and G taken together with the atom to which they are attached form a 5- to 6-membered ring containing 1 to 3 heteroatoms selected from O, N or S;
R a ′ represents hydrogen; or R a and R a ′ taken together with the atom to which they are attached form a 5- to 6-membered ring, optionally containing 1 to 3 heteroatoms selected from O, N or S;
R b represents (C 1 -C 6 )alkyl, optionally substituted with —C(O)NR x R y , —NR x R y , or carboxylic acid;
R c represents hydrogen; or R b and R c taken together with the atoms to which they are attached form a 5- to 6-membered ring containing 1 to 3 heteroatoms selected from O, N or S, wherein the 5- to 6-membered ring is optionally further substituted with hydroxyl;
R d represents (C 1 -C 6 )alkyl, optionally substituted with —OR x , carboxylic acid, or aryl-OH;
R e represents hydrogen; or R d and R e taken together with the atoms to which they are attached form a 5- to 6-membered ring containing 1 to 3 heteroatoms selected from O, N or S; and
R x and R y independently represent hydrogen, (C 1 -C 6 )alkyl or (C 2 -C 6 )acyl.
2. The method of claim 1 , wherein Z represents —NH-G.
3. The method of claim 1 , wherein G represents hydrogen or methyl.
4. The method of claim 1 , wherein Z represents —OH.
5. The method of claim 1 , wherein R a represents (C 1 -C 4 )alkyl, wherein (C 1 -C 4 )alkyl is substituted with —OH, —NR x R y , —NH—C(═NH)—NH 2 , —SR x , carboxylic acid, or aryl, wherein the aryl group is optionally further substituted with hydroxyl.
6. The method of claim 1 , wherein R a represents —CH 2 OH, —CH(CH 3 )OH, —(CH 2 ) 4 —NH 2 , —(CH 2 ) 2 —SCH 3 , —(CH 2 ) 2 C(O)OH, —(CH 2 ) 3 —NH—C(═NH)—NH 2 , —CH 2 -(phenyl), or —CH 2 -(p-OH(phenyl)).
7. The method of claim 1 , wherein R a and G taken together with the atoms to which they are attached form a 5- to 6-membered ring containing 1 to 3 heteroatoms selected from O, N or S.
8. The method of claim 1 , wherein R a and R a ′ taken together with the atoms to which they are attached form a 5- to 6-membered ring, optionally containing 1 to 3 heteroatoms selected from O, N or S.
9. The method of claim 1 , wherein R b represents (C 1 -C 4 )alkyl, wherein (C 1 -C 4 )alkyl is optionally substituted with —C(O)NR x R y , —NR x R y , or carboxylic acid.
10. The method of claim 1 , wherein R b represents sec-butyl, —CH 2 C(O)NH 2 , —(CH 2 ) 4 —NH 2 , —(CH 2 ) 4 —NH(C(O)CH 3 ), —CH 2 C(O)OH, or —(CH 2 ) 2 C(O)OH.
11. The method of claim 1 , wherein R b and R c taken together with the atoms to which they are attached form a 5- to 6-membered ring containing 1 to 3 heteroatoms selected from O, N or S, wherein the 5- to 6-membered ring is optionally further substituted with hydroxyl.
12. The method of claim 1 , wherein Y represents a group represented by the following structural formula
13. The method of claim 1 , wherein R d represents (C 1 -C 4 )alkyl, optionally substituted with —OH, —OCH 3 , —C(O)OH, or p-OH(phenyl); and R e represents hydrogen.
14. The method of claim 1 , wherein R d and R e taken together with the atoms to which they are attached form a 5- to 6-membered ring containing 1 to 3 heteroatoms selected from O, N or S.
15. The method of claim 1 , wherein:
Z represents —OH, or —NH-G;
G represents hydrogen or (C 1 -C 6 )alkyl;
Y represents a group represented by the following structural formula
R a represents (C 1 -C 6 )alkyl substituted with —OH, —NH 2 , carboxylic acid, guanidino, or phenyl;
R a ′ represents hydrogen; or R a and R a ′ taken together with the atom to which they are attached form a 5- to 6-membered ring, optionally containing 1 to 3 heteroatoms selected from O, N or S;
R b represents (C 1 -C 6 )alkyl, optionally substituted with —C(O)NR x R y or carboxylic acid;
R c represents hydrogen; or R b and R c taken together with the atoms to which they are attached form a 5- to 6-membered ring containing 1 to 3 heteroatoms selected from O, N or S;
R d represents (C 1 -C 6 )alkyl, optionally substituted with —OR x ;
R e represents hydrogen; or R d and R e taken together with the atoms to which they are attached form a 5- to 6-membered ring containing 1 to 3 heteroatoms selected from O, N or S; and
R x and R y independently represent hydrogen, (C 1 -C 6 )alkyl or (C 2 -C 6 )acyl.
16. The method of claim 1 , wherein:
Z represents —OH, or —NH-G;
G represents hydrogen or methyl;
Y represents a group represented by the following structural formula
R a represents —CH 2 OH, —CH(CH 3 )OH, —(CH 2 ) 4 —NH 2 , —(CH 2 ) 2 C(O)OH, —(CH 2 ) 3 —NH—C(═NH)—NH 2 , or —CH 2 -(phenyl);
R a ′ represents hydrogen;
R b represents —CH 2 C(O)NH 2 , —CH 2 C(O)OH, or —(CH 2 ) 2 C(O)OH;
R c represents hydrogen; or R b and R c taken together with the atoms to which they are attached to form a pyrrolidine ring;
R d represents sec-butyl, —CH 2 OH, or —CH(CH 3 )OH; and
R e represents hydrogen.
17. The method of claim 1 , wherein the compound is selected from:
Compound
No.
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
or pharmaceutically acceptable salt thereof.
18. The method of claim 1 , wherein the immune response is further mediated by the programmed cell death 1 (PD-1) signaling pathway.
19. The method of claim 1 , wherein the immune response is further mediated by an agent that modulates TIM-3 .
20. The method of claim 1 , wherein the subject is suffering from a disease or disorder selected from cancer, an immune disorder, an immunodeficiency disorder, an inflammatory disorder, an infectious disease, and transplant rejection; and the method treats the disease or disorder.
21. The method of claim 20 , wherein the disease or disorder is cancer.
22. The method of claim 21 , wherein the cancer is mediated by TIM-3 or an agent that modulates TIM-3.
23. The method of claim 21 , wherein the cancer is selected from breast cancer, colon cancer, liver cancer, ovarian cancer, prostate cancer, renal cancer, and uterine cancer.
24. The method of claim 21 , wherein the cancer is a hematopoietic cancer.
25. The method of claim 24 , wherein the hematopoietic cancer is selected from a lymphoma, B cell lymophoma, T cell lymphoma, Burkitt's lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, a leukemia, a myeloma, acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphoblastic leukemia (CLL), chronic myelomonocytic leukemia (CMML), multiple myeloma, myelodysplastic syndrome (MDS), and plasmacytoma.
26. The method of claim 21 , wherein the cancer is selected from ovarian cancer, colon cancer, breast cancer, lung cancer, a myeloma, a neuroblastic-derived CNS tumor, a monocytic leukemia, a B-cell derived leukemia, a T-cell derived leukemia, a B-cell derived lymphoma, a T-cell derived lymphoma, and a mast cell derived tumor.
27. The method of claim 21 , wherein the cancer is selected from blastoma, breast cancer, epithelial cancer, colon cancer, lung cancer, melanoma, prostate cancer, renal cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, uterine cancer, ovarian cancer, colorectal cancer, rectal cancer, cancer of the anal region, cancer of the peritoneum, connective tissue cancer eye cancer, throat cancer, oral cavity cancer, biliary tract cancer, stomach cancer, testicular cancer, carcinoma of the fallopian tubes, endometrial cancer, cervical cancer, vaginal cancer, vulval cancer, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, thyroid cancer, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma, cancer of the urethra, cancer of the penis, chronic or acute leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), myeloproliferative disorder/neoplasm (MPDS), myelodysplasia syndrome, a monocytic leukemia, a B-cell derived leukemia, a T-cell derived leukemia, solid tumors of childhood, a B-cell derived lymophoma, T-cell dervied lymphoma, Hodgkin's lymphoma, indolent and aggressive non-Hodgkin's lymphoma, Burkitt's lymphoma, follicular lymphoma, mesothelioma, thymic carcinoma, myeloma, multiple myeloma, giant cell myeloma, heavy-chain myeloma, light chain or Bence-Jones myeloma, a mast cell derived tumor, leiomyoma, leiomyosarcoma, glioma, cancer of the bladder, cancer of the ureter, carcinoma of the renal pelvis, liver cancer, pancreatic cancer, post-transplant lymphoproliferative disorder (PTLD), neuroblastic-derived CNS tumors, neoplasm of the central nervous system (CNS), tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, epidermoid cancer, salivary gland carcinoma, squamous cell cancer, abnormal vascular proliferation associated with phakomatoses, Meigs' syndrome, Merkel cell carcinoma, and environmentally induced cancers.
28. The method of claim 20 , wherein the disease or disorder is an infectious disease.
29. The method of claim 20 , wherein the disease or disorder is an immune disorder, immunodeficiency disorder, or an inflammatory disease.Cited by (0)
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